1. Field of the Invention
This invention concerns generally a drug and device combination system used in a method for treatment of severe and oral corticosteroid-dependent asthma and other respiratory diseases requiring a treatment with orally administered steroids. The method comprises administration of an inhalable corticosteroid drug by a flow rate and volume regulated inhalation wherein the inhalable corticosteroid is administered predominantly into a target area of the lungs, in particular the small airways of the lungs, using a system comprising an inhalable drug and device combination. The system permits fine tuning of the flow of the inhalable corticosteroid drug into the lungs in an optimized volume to secure a maximal and reproducible corticosteroid dose deposition into the lung target area. Both the method and the system are safe, efficacious, reproducible, controllable and individually programmable to assure treatment safety and compliance. The device's capability to control flow rate and inhalation volume assures delivery of the inhalable drug directly to the target area of the lungs and thereby minimizes the drug dose requirement of oral steroids while at the same time it maximizes the drug dose deposition in said target areas, assures the dose reproducibility, decreases drug waste and eliminates or greatly reduces side effects.
The drug and device combination system has unexpectedly large clinical benefits. When the patients are treated with this system according to the method of the invention and when the protocol of the invention for inhalable corticosteroids delivery is followed, the use of the drug and device combination system results in a complete weaning of the patients from oral corticosteroids in at least 50% of all treated patients, or in a partial weaning to ≦50% of the initial oral corticosteroid dose in about 80% of all treated patients. Concurrently, it results in a substantial improvement of FEV1—as well as in a clinically meaningful improvement of Quality of Life of these patients. There is a decreased degree of symptoms exacerbation and a decreased need for hospitalization. The device that provides a controlled and regulated flow rate and volume during inhalation assures a more homogeneous peripheral deposition of the drug, and its individually tailored programming based on the patient's health conditions provides a feedback regarding the adherence to the treatment protocol.
The method and system of the invention are particularly suitable for delivery of inhalable corticosteroids into the peripheral small airways of the lungs for treatment of severe and oral corticosteroid-dependent asthma and other respiratory diseases requiring treatment with oral corticosteroids, without the need for simultaneous administration of oral corticosteroids or with a significantly decreased need for such simultaneous administration of oral corticosteroids. The controlled flow rate and volume system significantly increases delivery of the drug and selectively delivers the aerosolized inhalable corticosteroid into the small airways, particularly to terminal and respiratory bronchioles and alveolar ducts and sacks of the peripheral lungs. It further eliminates or significantly decreases deposition of the corticosteroid into the larger bronchioles, bronchi and trachea of the upper lungs as well as into the oropharyngeal area and thereby substantially decreases or completely eliminates undesirable secondary symptoms, such as mouth irritation, thrush, oral candidiasis, hoarseness, soreness, upper respiratory tract infection, laryngitis, voice alterations or other oropharyngeal problems typically associated with delivery of inhalable corticosteroids. The method utilizes inhalation devices comprising components for individualization of treatment parameters in patients having compromised breathing pattern due to severe and oral corticosteroid-dependent asthma or another severe respiratory disease, and for assurance of compliance and safety.
The method of the invention includes a step of complete or at least partial weaning of a patient from orally administered steroids and replacing them with much lower doses of inhalable corticosteroids, wherein the unique drug and device combination results in an unexpectedly large improvement of pulmonary function, improvement in Quality of Life, particularly in asthmatic patients, unexpected and substantial reduction of symptom exacerbations, reduction in occurrence and length of hospitalizations and in recovery of endogenous hydrocortisone (cortisol) production.
2. Background and Related Disclosures
Asthma and particularly severe oral corticosteroid-dependent asthma is a chronic inflammation of the bronchial tubes of airways that causes swelling, bronchial narrowing and constriction resulting in severe breathing obstructions in asthmatic patients. The severe form of asthma is connected with bronchial hyper-reactivity and with chronic severe and oral corticosteroid-dependent asthmatic symptoms. Other respiratory diseases that require treatment with orally administered corticosteroids experience similar symptoms. Such symptoms are generally treated with orally administered or inhalable drugs, preferably with oral or inhalable steroids and corticosteroids suitable for inhalation therapy.
Global Initiative for Asthma (GINA) asthma guidelines has been established to determine severity of the asthma. Severe and oral corticosteroid-dependent asthma is classified by GINA guidelines as steps IV and V. For step IV, the preferred treatment is to combine medium to high doses of inhaled corticosteroid with a long-acting inhaled β-agonists. For step V, the above medication is further supplemented with orally administered corticosteroids. Both treatments are known to cause or to be associated with severe side effects, which exacerbate with a continuous and extended use of high doses of inhaled corticosteroids.
Successful treatment and management of severe asthma and other respiratory diseases is often dependent on orally administered corticosteroids. Severe oral corticosteroid-dependent asthma and other respiratory diseases require treatments with high doses of orally or intravenously administered steroids that are chemically and functionally similar to hydrocortisone hormones produced by the adrenal glands. However, the long-term use of these corticosteroids leads to serious undesirable side effects, such as truncal obesity, glaucoma, acceleration of cataract formation, high blood pressure, an increased risk of diabetes due to glucose intolerance and of osteoporosis due to bone mineral loss, psychological effects, growth suppression in children and adrenal suppression. These side effects have been linked with cortisol suppression, especially when dose levels of systemically administered corticosteroids are high.
Many attempts have been made to control asthma with a particular emphasis on the control and treatment of patients suffering from the severe and oral corticosteroid-dependent asthmatic attacks. However, since each individual is unique in his/her degree of reactivity to environmental triggers, asthma affects each patient differently. This naturally influences the type, dose and route of administration of various medications and treatments.
The currently available treatments for asthma are largely dependent on the severity of the disease. In most cases (GINA step II-V), these treatments involve administration of steroids, such as orally administered corticosteroids (OCS), such as prednisone or prednisolone, or inhalable corticosteroids (ICS), such as fluticasone, beclomethasone, budenoside, mometasone, ciclesonide, flunisolide or triamcinolone acetonide, in a therapeutic dose. These treatments may be supplemented with other drugs, such as, for example, bronchodilators such as β-agonists. Since orally or otherwise systemically delivered corticosteroids affect the whole body and cause rather severe adversary side effects and secondary symptoms, locally administered corticosteroids by inhalation are highly preferred as a current treatment for asthma.
Corticosteroids, also called glucocorticoids, are powerful drugs that quickly reduce inflammation and pain. However, the corticosteroids benefit is often negated by severe side effects observed during extended administrations of corticosteroids needed for treatment of recurring respiratory diseases such as, for example, severe and oral corticosteroid-dependent asthma. To maximize benefits of corticosteroids, but minimize their potential side effects, these drugs are usually prescribed in doses as low as possible and/or only for a short duration of time. Since the severe and oral corticosteroid-dependent asthma requires repeated administration of inhalable corticosteroids, there is a real danger of developing side effects such as mouth irritation, thrush, oral candidiasis, hoarseness, sore throat, coughing, upper respiratory tract infections, laryngitis or other oropharyngeal problems as well as other serious adverse reactions tiding osteoporosis, increased mortality, poisoning from the overdose of corticosteroids or exogenous Cushing's syndrome.
Moreover, when the administration of corticosteroids is stopped or decreased too rapidly, a life-threatening acute adrenal crisis may develop because the adrenal glands of the patient are unable to produce their own hormones fast enough. Acute adrenal crisis is a state caused by insufficient levels of the steroid hormone hydrocortisone (cortisol) also called stress hormone, produced by the zona fasciculata of the adrenal gland that is released in response to any stress situation. Risk factors for acute adrenal crisis include physical stress such as infection, trauma or surgery, adrenal gland or pituitary gland injury, and premature termination of treatment with steroids.
It would therefore be advantageous to have available a method and means for replacement, or at least reduction, of orally administered corticosteroids, including weaning of the patients of corticosteroids. Such method would be particularly useful for treatment of those patients suffering from severe and oral corticosteroid-dependent asthma and who are in need of a continuous corticosteroid treatment. It would further be advantageous for reduction of side effects associated with administration of large dosages of corticosteroids, if the dose of corticosteroids administered via inhalation could further be reduced by improved targeting of aerosolized drug particles to the small airways of the deep, peripheral lung.
As indicated already above, many attempts to successfully treat severe and oral corticosteroid-dependent asthma have been made. These attempts include development of new and more potent drugs, such as for example more potent corticosteroid fluticasone as well as new nebulizing technologies that affect pulmonary drug delivery.
Eur. J. Clin. Pharmacol., 57:637-41 (2001) describes a study comparing a large volume spacer and fluticasone nebulizer (FP-neb) in delivery of fluticasone propionate by inhalation in healthy volunteers. The large volume (750 ml) spacer was shown to produce about a sevenfold higher relative lung dose than nebulizer. This reference shows that the efficacy of the aerosol delivery depends on the device used for such delivery.
Respir. Med., 93(10):689-99 (1999) describes the oral steroid-sparing effect of a high dose (4000 μg/day/bid) and a lower dose (1000 μg/day/bid) of inhaled fluticasone propionate. The nebulized fluticasone at a daily dose between 1 mg (1000 μg) and 4 mg (4000 μg) was a safe and effective means for reducing the oral steroids requirement of patients with chronic oral dependent asthma. The reduction in the need for orally administered prednisone was significantly greater in the group receiving 4000 μg of fluticasone propionate per day than 1000 μg per day. However, a high percentage (37%) of all patients discontinued the 4000 μg treatment, presumably for high occurrence of severe side effects.
J. Allergy Clin. Immunol., 103:267-75 (1999) describes an oral corticosteroids-sparing effect and improved lung function in patients with severe chronic asthma who received 500 or 1000 μg of fluticasone propionate administered twice daily. While this treatment eliminated a need for oral prednisone, topical adverse effects associated with inhaled corticosteroids were observed during this treatment.
Br. J. Clin. Pract., 48:15-8 (1994) assessed a long-term safety of fluticasone propionate in asthmatic children. Adverse effects were reported by 51% of patients even with such low doses as 50 or 100 μg administered twice a day via a dry powder inhaler.
Cochrane Database Syst. Rev., (2004), Issue 3, Art. No.:CD002310 reviewed a potency of fluticasone propionate for treatment of chronic asthma and compared its effect to that of beclomethasone and budenoside. The study showed that fluticasone propionate, given at half the daily dose of beclomethasone or budenoside, resulted in improvement of forced expiratory volume in the first second (FEV1). Unfortunately, due to a larger deposition of the fluticasone in the upper lungs, it also had a higher risk of pharyngitis and other adverse side effects.
Cochrane Database Syst. Rev., (2005), Issue 3, Art. No.: CD003534 describes use of inhaled fluticasone at different doses. While patients receiving 2000 μg per day of fluticasone propionate were more likely to reduce a need for oral prednisolone then those on 1500 or 1000 μg/day, hoarseness and oral candidiasis were significantly greater for these higher doses.
Cochrane Database Syst. Rev., (2003), Issue 4, Art. No.: CD004109 investigated high dose versus low dose inhaled corticosteroid as initial starting dose for asthma in adults and children. 2000 μg fluticasone was administered once a day using AKITA protocol. This dose resulted in FEV1 improvement of 17.1% and reduction in oral steroid use of 33.2%. It was estimated that of the administered dose only 500-700 μg reached the central portion of the lungs, the same amount remained in the nebulizer and the remaining corticosteroid was deposited in oropharynx or exhaled. Although the FEV1 was improved with this high dose of fluticasone, the loss of the drug was approximately two-thirds of the total dose, with one third remaining in the nebulizer and one-third deposited in oropharynx thereby resulting in undesirable side effects.
Respiratory Medicine, 94: 1206-1214 (2000) investigated the efficacy and safety of nebulized fluticasone propionate compared to orally administered prednisolone. The nebulized fluticasone was at least as effective as oral prednisolone in the treatment of children with acute exacerbated asthma.
Annals Allergy, Asthma and Immunology, 92:512-522 (2004) reviewed the efficacy and safety of inhaled corticosteroids when used to reduce daily oral corticosteroid requirement in patients with severe asthma. Authors concluded that inhalable corticosteroid can reduce orally administered corticosteroids requirements in patients with persistent and exacerbated asthma. However, the question of increased adverse side effects still remains.
The US patent application publication No.: 20050087189 A1 describes an inhalation device which emits aerosol only during the first half of the patient's inspiration time which is used to administer budesonide to asthmatic children. The results suggested that lower daily doses could be used and that the compliance was better than in case of nebulizers which emit aerosol continuously. However, US 20050087189 A1 does not disclose any flow rate and/or volume control of the device. It is further not disclosed that any of the children could be weaned from any orally administered corticosteroids partially or completely, using the device and method described in US 20050087189 A1.
Respir. Med., 86(2):105-8 (1999) demonstrated, in an open label-study, that a nominal dose of 4-8 mg budesonide daily, given via conventional nebulizer (which was not specified in the publication) will, over a period of 12-18 months, lead to steroid weaning in 14 of the 18 subjects studied. There were also only moderate improvements in pulmonary function, along with a reduction of the mean annual number of asthma exacerbations requiring hospitalization, from 1.5 to 0.9 per year. The relatively high dose (up to 8 mg) and volume in the nebulizer (16 mL) will demand very long inhalation times of more than 30-35 min per treatment. In addition, side effects like oral thrush or disturbing sore throat occurred in 11% of the subjects treated. Milder side effects such as hoarseness and mild thrush were also reported, but not quantified.
The above discussed disclosures concern administrations of steroids to asthmatic patients and efficacies thereof in reducing the concurrent use of orally administered steroids. These disclosures indicate that the need for orally administered steroids in patients suffering from severe and oral corticosteroid-dependent asthma may be decreased by administration of appropriately high doses of inhalable corticosteroids. However, when such high doses of inhalable corticosteroids are administered, severe adverse side reactions still occur, preventing a truly efficacious treatment of these patients.
It would be therefore advantageous to have available a controlled system comprising a drug and device combination and a method including a treatment protocol that would assure compliance with preset treatment conditions. Such system would provide and assure delivery of an efficacious dosage of the inhalable corticosteroid to small airways of the deep peripheral lung predetermined target area, without at the same time depositing the drug in oropharyngeal area in order to reduce or eliminate undesirable adverse side reactions and secondary symptoms. Clearly, such system would depend on the exclusive and precise delivery of these drugs to said target area of the lungs and also on inhalation devices and apparatuses used for such delivery. Numerous attempts were made to provide devices for precise administration of drugs to the lungs; however, these attempts lack efficacy, targeted delivery to deeper lung areas, elimination of adverse reactions and individualization of such treatment.
In this regard, U.S. Pat. No. 6,606,989 discloses a device for precise administration of medicated aerosol to the lungs. The device comprises of an inhalation mouthpiece; a pressure sensor responsive to a suction pressure to produce a triggering signal; an adjustable vaporizer coupled to the inhalation mouthpiece containing the inhalable fluid that issues frequencies to deliver the vaporized fluid to the mouthpiece; a compressed-air control valve responsive to a valve signal to provide a predetermined inhaled volume; a volumetric flow controller coupled to the compressed-air control valve to preset a determined quantity of a volumetric flow of the nozzle flow; a flow meter for control of a predetermined volumetric flow; and an electronic controller that receives the triggering signal from the pressure sensor to produce the valve signal and the vaporizing signal. The electronic controller is configured with a pre-settable vaporizing period and a pre-settable pause interval. It further controls the high frequencies issued by the vaporizer and is operable to set the vaporizing period of the adjustable vaporizer to an invariable value from opening of the compressed-air control valve and causes a predetermined volume to be emitted at the device's mouthpiece for each respiratory maneuver. While this disclosure certainly provides a useful device for inhalation, it lacks the aerosol having a limited particle size range permitting targeted delivery of the drug into the peripheral lungs and does not provide an individual control for compliance with the drug delivery protocol. Moreover, U.S. Pat. No. 6,606,989 does not disclose any specific values for flow rate and/or volume which would improve the deposition of aerosolized particles in the target area of the lower lungs, in particular the small airways.
J. Physiol. Pharmacol., 58 (Supp1.5): 615-625 (2007) describes novel approaches to enhance pulmonary delivery of proteins and peptides. This article describes importance of a number of biophysical and physiological parameters that have to be considered when the delivery of proteins and peptides into systemic circulation is contemplated. Among these parameters are particle diameter, particle density, hygroscopicity, electrical charge, chemical properties of the drug, age of the patient, pulmonary disease, breathing pattern, all of which affect the mechanism of pulmonary drug deposition. The article discloses one type of the AKITA® inhalation systems that guides the patient through the inhalation maneuver and ensures an optimized particle deposition.
For treatment of severe and oral corticosteroid-dependent asthma, the above devices might be somehow useful; however, to achieve the reduction or elimination and weaning of the patient from the orally administered corticosteroids, these devices are not efficacious enough without further modifications, adjustments, additional components and without a precise protocol for inhalable corticosteroids delivery.
It would, therefore, be advantageous to have available a combination system including an inhalation device, an inhalable corticosteroid and a method that would provide efficacious treatment for severe and oral corticosteroid-dependent forms of asthma with an efficacious dose of said inhalable corticosteroid selectively deposited at a site of asthmatic inflammation, namely in alveoli and bronchioles of the small airways of the lower, peripheral lungs, combined with no or low deposition of the corticosteroid in the nose, mouth, throat, oropharyngeal area, larger bronchioles, bronchi, and trachea, wherein the need for concurrent orally administered steroids could be eliminated or the need for the oral dose of these drugs could be at least significantly reduced in the oral corticosteroid-dependent asthma patient population. As a consequence, the oropharyngeal side effects enumerated above will be reduced.
It is, therefore, a primary object of this invention to provide a combination system including an inhalation device, an inhalable corticosteroid, a method for treatment and a protocol for precise and efficacious delivery of said inhalable corticosteroid into the small airways of the lungs for the treatment of severe and oral corticosteroid-dependent forms of asthma and other respiratory diseases. The system delivers a sufficiently high dosage of the inhalable corticosteroid to treat these conditions, including severe and corticosteroid-dependent asthma, to permit either a complete elimination and weaning of the patients from oral corticosteroids in at least 50% of all treated patients or reduction of the oral corticosteroid dose in about 80% of all patients, with a mean reduction of the initial dose of about 75%. Additionally, said system achieves a maximal deposition of the inhalable corticosteroid in the lower, peripheral lung, controlled dose reproducibility, reduced variability of lung dose deposition and minimization of side effects. The system delivers the corticosteroids selectively into the small airways of the peripheral lungs (also called lower lungs) of an asthmatic patient without depositing said inhalable corticosteroid into the upper lungs, trachea, mouth, nose or oropharyngeal cavity, and thus without causing undesirable side effects, and it greatly improves the physiological parameters of treated patients.